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PubMed2000

Effect of testicular capsulotomy on secretion of testosterone and gonadotrophins in rats.

AIM: In order to clarify further the mechanisms underlying the effect of capsulotomy on testicular function, the levels of testosterone, LH and FSH were observed. METHODS: Intratesticular testosterone levels and LH, FSH levels in the peripheral blood of normal, sham-operated and capsulotomized rats were detected by RIA. RESULTS: After testicular capsulotomy, there was a progressive reduction in the testosterone level in the testicular venous blood together with a progressive increase in the LH and FSH levels in the peripheral blood from approximately 30 days post-capsulotomy. Morphological changes were observed at 5-10 days after capsulotomy, i.e., far ahead of the hormonal changes. CONCLUSION: The seminiferous tubular damage after testicular capsulotomy was not caused by the reduction in testosterone, and on the contrary, the hormonal change might be secondary to the morphological alterations. The increase in LH level most likely resulted from a negative feedback influence from the lowered testosterone level, while the increase in FSH secretion may be a feedback signal of the damaged seminiferous tubules.

Animals↗
PubMed1997

Melatonin receptors are present in adult rat Leydig cells and are coupled through a pertussis toxin-sensitive G-protein.

Previous studies have suggested that melatonin (MLT) acts directly on rat Leydig cells by modulating androgen production. In the present study, the site of action of MLT was investigated. The binding of 2-[125I]iodomelatonin (125I-MLT; 7-240 pmol/l) to Leydig cell membrane fragments was tested in the presence or absence of guanosine 5'-O-(3-thiotriphosphate) (GTP-gamma-S; 50 mumol/l). Saturation studies and Scatchard analysis revealed the existence of a high-affinity binding site with a Bmax of 46.70 +/- 3.50 fmol/mg protein and a Kd of 88.70 +/- 6.20 pmol/l; treatment with GTP-gamma-S reduced the concentration of 125I-MLT binding sites (Bmax 34.03 +/- 4.50), while increasing the Kd to 106.5 +/- 2.61 pmol/l. Pretreatment of the cells with pertussis toxin (PTX; 10 ng/ml for 16 h) resulted in a decreased binding of 125I-MLT and a lack of effect of GTP-gamma-S. Moreover, the effect of MLT on testosterone secretion induced by LH (30 mIU/ml), forskolin (1 mumol/l) and LHRH (100 nmol/l) was studied after 3-h incubation of cells which had been precultured with or without PTX. The inhibition of testosterone secretion due to MLT administration was eliminated by PTX pretreatment during forskolin and LH, but not during LHRH administration. However, 17-hydroxyprogesterone levels were higher in all groups incubated in the presence of MLT, irrespective of PTX pretreatment. Our data suggest that: (a) MLT receptors are present on the membranes of adult rat Leydig cells; (b) they couple through PTX-sensitive G-protein-coupled binding sites; (c) the mechanism by which MLT blocks 17-20 desmolase enzymatic activity (thus leading to increased 17-hydroxyprogesterone levels), and testosterone secretion during LHRH stimulation is likely to depend on one or more different mechanism(s) of action.

Animals↗
PubMed1984

Effects of antimicrotubular agents in cAMP production and in steroidogenic response of isolated rat Leydig cells.

In dispersed rat Leydig cells, colchicine was found to stimulate basal cAMP production and testosterone secretion in a dose and time-dependent manner, but to a lesser extent than LH. However, these drugs are unable to stimulate adenylate cyclase activity in plasma membranes isolated from these cells. The amount of testosterone secreted at 150 min under the influence of colchicine and LH added simultaneously was not different from the amount produced during stimulation by LH alone. It is only after exposure of the cells for 1 hr to colchicine that the accumulation of cAMP in response to LH was inhibited; furthermore, both intracellular and medium testosterone accumulation in response to the hormone were reduced. Similar effects were observed with two other alkaloids, vinblastine and podophyllotoxin. The three drugs also inhibited the stimulation of testosterone secretion by 8-Br-cAMP or choleratoxin. These studies suggest that the state of microtubule polymerization and/or tubulin can influence the process of steroidogenesis in rat Leydig cells.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1982

Stimulatory effect of LHRH and its agonists on Leydig cell steroidogenesis in vitro.

Short-term (4 h) incubation of collagenase-dispersed Leydig cells from adult rats in the presence of an LHRH agonist caused a 2-3-fold stimulation (P less than 0.001) of testosterone production. This effect was dose-dependent and as little as 5 x 10(-11) M LHRH agonist caused significant stimulation whilst maximal effects were achieved with 10(-9) M concentrations. Stimulation of steroidogenesis by LHRH agonist was prevented by addition of an antiserum specific for the peptide, but was exaggerated in the presence of the phosphodiesterase inhibitor MIX, suggesting the involvement of cyclic AMP in the response of the Leydig cells to the agonist. Native LHRH caused a similar degree of stimulation of testosterone secretion to LHRH agonist but concentrations 1000 times greater than those of the agonist were required to achieve this, a finding consistent with the known affinities of these 2 peptides for the Leydig cell LHRH-receptor. The addition of LHRH agonist also enhanced (P less than 0.001) testosterone secretion by adult rat Leydig cells in response to hCG or dibutyryl cyclic AMP, and this effect was still evident in the presence of maximally-stimulating concentrations of these factors. LHRH agonist also stimulated testosterone secretion by Leydig cells from immature rats, but this effect differed from that in the adult in being of smaller magnitude and being restricted to effects on basal secretion or secretion elicited by low concentrations of hCG. These results show for the first time (a) that LHRH and its agonists can exert effects on Leydig cell steroidogenesis during short-term incubation, and (b) that these effects are stimulatory, which contrasts with the inhibitory effects reported after long-term (2-3 days) exposure of Leydig cells to LHRH agonists in vivo and in vitro. The availability of this simple and rapid measure of a biological action of LHRH on the Leydig cell should enable its precise mode of action to be determined, and should throw light on the physiological role of endogenously produced testicular 'LHRH'.

1-Methyl-3-isobutylxanthine↗
PubMed1994

Comparative aspects of 11 beta-hydroxysteroid dehydrogenase. Testicular 11 beta-hydroxysteroid dehydrogenase: development of a model for the mediation of Leydig cell function by corticosteroids.

It has been shown that stress or disease-induced increases in plasma corticosterone result in diminished testosterone secretion from the testes. This article reviews investigations from our laboratories that explore the role of 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) in this process. It is proposed that the level of 11 beta-OHSD in Leydig cells dictates the level of intracellular glucocorticoid available to the glucocorticoid receptor and thus the potency of corticosteroid as an inhibitor of testosterone secretion. Stressed and unstressed rats were housed under simulated natural conditions in a Visible Burrow System. Stressed animals showed elevated plasma corticosteroid, lowered plasma testosterone, and diminished testicular 11 beta-OHSD, Immunocytochemical analysis showed that only Leydig cells of the rat testis contain 11 beta-OHSD and glucocorticoid receptors. Half-maximal inhibition of testosterone by Leydig cells required 1.5 nM dexamethasone or 0.4 microM corticosterone. Glycyrrhetinic acid, an inhibitor of 11 beta-OHSD, increased the potency of corticosterone, but did not affect dexamethasone based inhibition. The glucocorticoid receptor blocker, RU 486, prevented inhibition by both corticosterone and dexamethasone. Other classes of steroid were not inhibitors of testosterone biosynthesis. Thus, 11 beta-OHSD oxidizes corticosterone to the inactive metabolite 11-dehydrocorticosterone, relieving steroid-dependent inhibition of Leydig cell function. Lowered enzyme activity increases glucocorticoid dependent inhibition of testosterone production. We conclude that the evidence supports a role of 11 beta-OHSD in testosterone secretion by the testes.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1999

The effects of 2-bromopropane on viability and testosterone production ability of rat Leydig cells in primary culture.

Epidemiological surveys and animal experiments have shown that 2-bromopropane induces oligozoospermia in exposed workers and inhibits spermatogensis in laboratory animals. However, the mechanism by which 2-bromopropane exerts its effects is unknown. To this end, we examined the formation of testosterone by the Leydig cells and their survival of these cells in the presence of different concentrations of 2-bromopropane in vitro. Leydig cells were isolated following vascular perfusion, enzymatic dissociation and Percoll gradient centrifugation techniques. The cells were cultured in culture dishes. After 8 h, different cultures were exposed to 2-bromopropane at concentrations of 0.01 mmol/L, 0.10 mmol/L and 1.00 mmol/L. In order to stimulate Leydig cells to secrete testosterone, human chorionic gonadotropin (hCG) was also added. Cell viability was determined using the trypan blue dye exclusion test and cell numbers were counted by hemocytometer. Testosterone secretion was detected by radioimmunoassay. The cell viability decreased after exposure to 2-bromopropane in a dose-dependent way, but no morphological change was observed. The cell number decreased in the 2-bromopropane-treated cultures. The secretion of testosterone did not manifest defectable changes in the culture treated with 0.10 mmol/L and 0.01 mmol/L of 2-bromopropane; however, it decreased significantly (P < 0.02) in the presence of 1.00 mmol/L. Therefore, our results strongly suggest that 2-bromopropane may exert its cytotoxic effects on Leydig cells in vitro. We speculate that the decrease in the numbers of Leydig cells caused by 2-bromopropane was mediated by a feedback mechanism resulting from a lower testosterone concentration.

Animals↗
PubMed2004

[Effects of extrahypothalamic brain lesions on testicular function in rats--with special emphasis on asymmetry].

INTRODUCTION: The aim of our studies was to investigate the involvement of extrahypothalamic brain structures in the control of testicular functions with special emphasis on the effect of right- and left-sided structures. MATERIAL AND METHOD: We performed lesion of the insular cortex, the amygdala, interrupted part of nerve fibers to and from the insular cortex, and cut the major commissural pathway of the brain the corpus callosum in adult male rats and studied the effect of the interventions on testicular steroidogenesis, serum testosterone and gonadotrop hormone concentrations. RESULTS: Following lesion of the insular cortex on the right side serum testosterone level and steroidogenesis of the testes decreased (in the case of the left testis the difference was significant). Similar lesion on the left side did not change the parameters studied. Both right- and left-sided lesion induced a significant increase in serum LH concentration. The effect was more pronounced after right-sided lesion. Interruption of nerve fibers above the amygdala by a paramedian sagittal knife cut on the right or on the left side resulted in opposite effect on testicular steroidogenesis: right-sided intervention increased while left-sided one reduced testosterone secretion. Only left-sided cut influenced (decreased) serum testosterone level. There was no changes in LH concentration. Both right- and left-sided lesion of the amygdala induced a significant decrease in basal testosterone secretion in vitro of both testes and in serum testosterone level. However, serum LH concentration decreased only after left-sided surgery. Interruption of the corpus callosum in animals with left-sided orchidectomy induced a significant rise in steroidogenesis of the remaining (right) testis. Both sham surgery and callosotomy combined with left orchidectomy resulted in a significant increase in serum FSH level. CONCLUSION: Results of our studies suggest that extrahypothalamic brain structures and interventions influence endocrine functions of the testis through the hypothalamo-hypophyseal-testicular axis and by a direct neural route. Certain components of the regulatory system exhibit functional asymmetry.

Amygdala↗
PubMed2004

Retinoid-sensitive steps in steroidogenesis in fetal and neonatal rat testes: in vitro and in vivo studies.

Retinoic acid (RA) was recently shown to modify testosterone secretion of the fetal testis in vitro. We characterized this effect by culturing rat testes explanted at various ages, from Fetal Day 14.5 to Postnatal Day 3. In basal medium, RA inhibited, in a dose-dependent manner, both basal and acute LH-stimulated testosterone secretion by testes explanted on Fetal Days 14.5, 15.5, and 16.5. It had no effect on testes from older animals. The negative effect of RA did not result from a diminution in the number of Leydig cells but from a decrease in P450c17 mRNA levels and in LH-stimulated cAMP production. However, the RA-induced decrease in P450C17 mRNA levels was also observed with neonatal testes, suggesting that this enzymatic step is no longer rate limiting at this developmental stage. To study the physiological relevance of RA effects, we used fetuses and neonates issued from mothers fed a vitamin A-deficient (VAD) diet, resulting in a threefold decrease of plasma retinol concentration. On Fetal Day 18.5 and on Posnatal Day 3, testosterone secretion by the testis ex vivo was significantly increased in VAD animals. This shows that the endogenous retinol inhibits differentiation and/or function of fetal Leydig cells before Fetal Day 18.5 and is required for the normal regression of fetal Leydig cell function that occurs after Fetal Day 18.5. In conclusion, our results show that retinoids play a negative role on the steroidogenic activity during the differentiation of rat fetal Leydig cells.

Animals↗
PubMed1988

Effects of photoperiod, beta-endorphin, and naloxone on in vitro secretion of testosterone in white-footed mouse (Peromyscus leucopus) testes.

The effects of the pro-opiomelanocortin-derived beta-endorphin (B-EP) and the opioid antagonist naloxone on in vitro secretion (accumulation of testosterone (T) in the medium) of T by testicular cells were assessed in adult white-footed mice (Peromyscus leucopus). Animals were housed under long days (16L:8D) to maintain testicular function or under short days (8L:16D) to induce gonadal regression. In vitro treatment with B-EP or naloxone did not affect basal secretion of T in dispersed cells from active or regressed testes. However, B-EP caused a dose-dependent reduction in secretion of T from cells stimulated maximally with human chorionic gonadotropin (hCG) or dibutyryl cyclic adenosine 3', 5'-monophosphate (dbcAMP). Conversely, naloxone enhanced maximal hCG- and dbcAMP-stimulated secretion of T in testicular incubates from both long- (1.5-fold) and short-day (3.5-fold)-exposed mice. The finding that the addition of naloxone to maximally stimulated cells increased further the secretion of T is evidence that B-EP may act to inhibit gonadotropin-stimulated secretion of T. Also, the stimulatory effect of naloxone on cells from regressed testes indicates that B-EP may be involved in suppressing production of T during the gonadally regressed state. Testicular B-EP-like immunostaining is present within the cytoplasm of interstitial cells and is not apparent in the seminiferous tubules. Together, these results support the idea that in P. leucopus endogenous opioid peptides in the testes may aid in the regulation of testicular function throughout the yearly breeding cycle.

Animals↗
PubMed1985

In vitro steroid secretion by intact bovine ovarian follicles in a superfusion system.

A superfusion system for single intact follicles is described. Bovine follicles were superfused for 5 to 10 hours. Progesterone and testosterone secretion was stable after an adaptation period of 150 min. A 5-minute stimulation with hCG resulted in a 2-fold increase in progesterone secretion. Superfusion for 450 minutes of 3 small follicles of similar size and in the same ovary next to each other showed different secretion patterns of progesterone and testosterone. Superfusion for 150 minutes of follicles obtained from 2 pairs of ovaries showed that follicular size is not a sufficient criterion to predict the progesterone and testosterone secretion pattern. Closeness of follicles (big or small) to a corpus luteum did not impair their ability to secrete progesterone and testosterone. It is concluded that a superfusion system as has been described in this report is an effective and desirable method to study the physiology and pathophysiology of single intact follicles.

Animals↗
PubMed1984

Modulation of pulsatile gonadotropin secretion by testosterone in man.

In experimental animals, primary testicular deficiency leads to increased LH pulse frequency. Pulsatile FSH secretion has not been well characterized in any species. To determine the effect of testosterone (T) on the pattern of pulsatile gonadotropin secretion in man, we performed frequent blood-sampling studies in six normal men and six men with primary hypogonadism. All primary hypogonadal men were studied 6-8 weeks after stopping T replacement therapy. Five of the six hypogonadal men were restudied 6-8 weeks after treatment with T enanthate (200 mg, im, every 2 weeks; sampling in this group was 2 weeks after their last T injection). Blood sampling was done at 10-min intervals for 12 h in all subjects, and the pattern of episodic LH and FSH secretion was determined. Normal men had a serum T level of 6.3 +/- 0.3 ng/ml (mean +/- SEM), a LH level of 34 +/- 3 ng/ml, and a LH pulse pattern characterized by low frequency (7.6 +/- 0.7 pulses/12 h) and low amplitude (16 +/- 1 ng/ml). Compared to normal men, primary hypogonadal men had a significantly lower T level (2.9 +/- 0.4 ng/ml) and significantly higher LH pulse frequency (13.0 +/- 1.3 pulses/12 h), amplitude (51 +/- 7 ng/ml), and mean level (222 +/- 26 ng/ml). Reinstitution of T replacement therapy in hypogonadal men resulted in a significant increase in the T level (4.7 +/- 0.5 ng/ml) and significant decreases in LH pulse frequency (7.2 +/- 1.6 pulses/12 h) and amplitude (41 +/- 5 ng/ml) as well as mean LH level (75 +/- 15 ng/ml). FSH levels fluctuated in a distinctly pulsatile pattern in all three groups. Differences in pulsatile FSH secretion between primary hypogonadal men before and during T therapy and normal men paralleled those in pulsatile LH secretion in both frequency and amplitude. These results demonstrate that in man 1) diminished T negative feedback results in high frequency (circhoral), high amplitude LH and FSH pulses; 2) T replacement decreased LH and FSH pulse frequency and amplitude as well as mean levels; and 3) the decreased LH and FSH pulse frequency with T treatment implies that T or a metabolite of T acts on the central nervous system to slow the hypothalamic LHRH pulse generator.

Adult↗
PubMed1996

Role of P2-purinergic receptors in rat Leydig cell steroidogenesis.

The present study investigated the effects of extracellular ATP on the intracellular calcium ion concentration ([Ca2+]i) and testosterone production in isolated adult rat Leydig cells. This nucleotide caused an increase in [Ca2+]i, with a maximal effect at a concentration of 100 microM ATP, comprising a rapid initial spike followed by a long-lasting plateau. The first rapid spike was dependent on the release of Ca2+ from internal stores, since it also occurred in Ca(2+)-free medium and was abolished after depletion of internal stores with thapsigargin. The second, long-lasting, phase was dependent on the influx of Ca2+ from the extracellular medium. After 3 h of incubation, extracellular ATP stimulated testosterone secretion in a dose-dependent manner, with a maximal effect at 100 microM. Activation of steroidogenesis by ATP was fully dependent on the presence of Ca2+ in the external medium. Among different nucleotides, only ATP, adenosine 5'-[gamma-thio]triphosphate, UTP, benzoylbenzoic-ATP and 2-methylthio-ATP were effective in inducing both the rise in [Ca2+]i and testosterone secretion. These effects were blocked by preincubation of Leydig cells with oxidized ATP, an inhibitor of the P2Z-purinergic receptor subtype. These results show that rat Leydig cells possess P2-purinergic receptors whose activation triggers an increase in [Ca2+]i due to the release of Ca2+ from internal stores and Ca2+ influx from the external medium. The stimulatory effect of extracellular ATP on testosterone secretion seems to be coupled to the influx of Ca2+ from the external medium.

Adenosine Triphosphate↗
PubMed2001

Store-operated calcium influx and stimulation of steroidogenesis in rat Leydig cells: role of Ca(2+)-activated K(+) channels.

This study evaluates the role of internal calcium store depletion in the activation of ionic fluxes and steroidogenesis in adult rat Leydig cells. Thapsigargin and cyclopiazonic acid, two inhibitors of Ca(2+)-adenosine triphosphatase of internal Ca(2+) stores induced a dose-dependent rise in intracellular Ca(2+) concentrations following kinetics that would not be expected if the calcium rise was dependent only on internal calcium store depletion, but it was in keeping with the presence of calcium influx from the external medium. In fact, chelation of external calcium with EGTA during the plateau phase reduced the intracellular calcium concentration to basal levels. When added in calcium-free medium, thapsigargin and cyclopiazonic acid still induced a rise in the intracellular calcium concentration that was transient, and when calcium was added back to the medium, a rapid and sustained intracellular calcium increase was observed. Thapsigargin and cyclopiazonic acid induced a dose-dependent rise in testosterone secretion in the presence and absence of calcium in the external medium, although in calcium-free medium this stimulatory effect was lower. Leydig cell plasma membrane potential monitoring demonstrated that thapsigargin and cyclopiazonic acid induced first a rapid hyperpolarization, followed by a sustained depolarization phase that was reversed by the addition of the calcium-chelating agent EGTA. In the absence of calcium in the external medium the first phase of hyperpolarization was still present, but it was not followed by plasma membrane depolarization but by the slow return of plasma membrane potential to resting levels. The readdition of calcium to the external medium induced the rapid plasma membrane depolarization. Plasma membrane hyperpolarization was completely abolished by Leydig cell preincubation with the K(+) channel blockers tetraethylammonium and charybdotoxin. Leydig cell preincubation with K(+) channel inhibitors reduced the thapsigargin-stimulated Ca(2+) influx from the external medium and testosterone secretion. These results suggest that internal Ca(2+) stores depletion in rat Leydig cells induces a rise in intracellular Ca(2+), determining important plasma membrane potential variations that influence testosterone secretion.

Animals↗
PubMed2001

Molecular mechanisms of leptin action in adult rat testis: potential targets for leptin-induced inhibition of steroidogenesis and pattern of leptin receptor messenger ribonucleic acid expression.

Leptin, the product of the ob gene, is a pivotal signal in the regulation of neuroendocrine function and fertility. Although much of the action of leptin in the control of the reproductive axis is exerted at the hypothalamic level, some direct effects of leptin on male and female gonads have also been reported. Indeed, recent evidence demonstrated that leptin is able to inhibit testosterone secretion at the testicular level. However, the molecular mechanisms behind this effect remain unclear. The focus of this study was twofold: (1) to identify potential targets for leptin-induced inhibition of steroidogenesis, and (2) to characterize in detail the pattern of expression and cellular distribution of leptin receptor (Ob-R) mRNA in adult rat testis. In pursuit of the first goal, slices of testicular tissue from adult rats were incubated with increasing concentrations of recombinant leptin (10(-9)--10(-7 )M) in the presence of human chorionic gonadotropin (hCG; 10 IU/ml). In this setting, testosterone secretion in vitro was monitored, and expression levels of mRNAs encoding steroidogenic factor 1 (SF-1), steroidogenic acute regulatory protein (StAR), cytochrome P450 cholesterol side-chain cleavage enzyme (P450 scc) and 17 beta-hydroxysteroid dehydrogenase type III (17 beta-HSD) were assessed by Northern hybridization. In pursuit of the second goal, the pattern of cellular expression of the Ob-R gene in adult rat testis was evaluated by in situ hybridization using a riboprobe complementary to all Ob-R isoforms. In addition, testicular expression levels of the different Ob-R isoforms, previously identified in the hypothalamus, were analyzed by means of semi-quantitative RT-PCR. In keeping with our previous data, recombinant leptin significantly inhibited hCG-stimulated testosterone secretion. In this context, leptin, in a dose-dependent manner, was able to co-ordinately decrease the hCG-stimulated expression levels of SF-1, StAR and P450 scc mRNAs, but it did not affect those of 17 beta-HSD type III. In situ hybridization analysis showed a scattered pattern of cellular expression of the Ob-R gene within the adult rat testis, including Leydig and Sertoli cells. In addition, assessment of the pattern of expression of Ob-R subtypes revealed that the long Ob-Rb isoform was abundantly expressed in adult rat testis. However, variable levels of expression of Ob-Ra, Ob-Re, and Ob-Rf mRNAs were also detected, whereas those of the Ob-Rc variant were nearly negligible. In conclusion, our results indicate that decreased expression of mRNAs encoding several up-stream elements in the steroidogenic pathway may contribute, at least partially, to leptin-induced inhibition of testicular steroidogenesis. In addition, our data on the pattern of testicular expression of Ob-R isoforms and cellular distribution of Ob-R mRNA may help to further elucidate the molecular mechanisms of leptin action in rat testis.

17-Hydroxysteroid Dehydrogenases↗
PubMed1987

Modulation of gonadotropin secretion by corticosterone: interaction with gonadal steroids and mechanism of action.

The effects of corticosterone (B) on pituitary responsiveness to LHRH and on gonadal steroid modulation of gonadotropin secretion were investigated using primary cultures of rat pituitary cells. Cultures were treated for 2 days with steroids and then challenged with LHRH for 4 h. B inhibited LH secretion, increasing the EC50 for LHRH from 1.40 to 4.96 nM. The reduction in LH release was accompanied by an increase in cell LH, so that the total amount of LH present in the cultures was unchanged. The EC50 for the effect of B on LH secretion was 0.57 microM. B increased the total amount of FSH present in the cultures. At high concentrations of B (10-100 microM), this effect was associated with an increase in FSH secretion. Testosterone inhibited LH secretion in both the absence and the presence of B. B had no effect in the presence of maximal concentrations of testosterone but augmented the inhibitory effect of lower concentrations. Estradiol (E) stimulated LH secretion in both the absence and the presence of B. However, the stimulatory effect of E was reduced by B, so that cultures treated with both B and E secreted no more LH than untreated cultures. B inhibited the LH secretory responses to Ca2+ influx and protein kinase C activation but did not affect the response to arachidonic acid, suggesting that the mechanism of B action may involve an inhibition of arachidonic acid release. Together these results indicate that the inhibitory effects of stress on reproduction are mediated at least partially by the inhibitory effects of B on LH secretion.

Animals↗
PubMed1997

Novel modalities for appraising individual and coordinate pulsatile hormone secretion: the paradigm of luteinizing hormone and testosterone release in the aging male.

To quantify aging- and disease-associated alterations in the integrative and interactive components of a pulsatile neuroendocrine axis, novel biomathematical strategies are required. Here, I illustrate as an investigative paradigm otherwise subtle aging-dependent disturbances of the gonadotropin-releasing-hormone (GnRH)-luteinizing hormone (LH)-testosterone feedback axis in men, in whom strong age-related contrasts become evident via any of four strategies applied alone or in combination: (1) intensified blood sampling schedules to capture the temporal structure of episodic hormone (LH and testosterone) secretion; (2) deconvolution analysis as a technique to quantify underlying pituitary and gonadal hormone secretory rates from the observed plasma hormone concentration profiles; (3) approximate entropy as a scale- and model-independent measure of the serial regularity or orderliness of the hormone release process over time; and (4) cross-approximate entropy (cross-ApEn) to quantify joint asynchrony between two concurrent pulse trains without confounding by variable lag. These new methodologies are introduced and reviewed briefly, a stochastic differential equation feedback construct alluded to, and the resultant insights into distinct alterations of the aging male gonadotropic axis highlighted. In summary, the new experimental strategies of intensified venous sampling, multiparameter deconvolution analysis, approximate entropy, and cross-approximate entropy unveil new mechanisms underlying dynamic neuroendocrine-axis activity, as exemplified by aging-associated disruption of the human male reproductive axis.

Aging↗
PubMed1980

Relation of neuroendocrine system to the reproductive decline in aging rats and human subjects.

The relation of neuroendocrine functions to the reproductive decline was compared in human subjects and in rats of both sexes. The ovaries of rats remain potentially functional throughout the animal's life span, but cease to exhibit regular 4- or 5-day cyclic changes at about midelife. The loss of estrous cycles is believed to be due primarily to changes in hypothalamic neurotransmitters that lead to failure to exhibit cyclic surges in release of hypothalamic luteinizing hormone-releasing hormone and pituitary gonadotropins. Menstrual cycles normally cease in women between 40 and 50 years of age, primarily because the ovaries decline in their capacity to respond to gonadotropic stimulation with adequate production of estrogen and progesterone, and by ovulation, which in turn leads to increased gonadotropin secretion. In aging male rats, testosterone secretion by the testes decreases due to reduced stimulation by gonadotropins, in turn caused by decreased hypothalamic stimulation. Elderly men have been reported to show a reduction in testosterone and sperm production, accompanied by an increase in gonadotropin secretion, but more recent work in healthy, active men showed no increase in testosterone secretion with age.

Aging↗
PubMed1999

Developmental changes of hypothalamic, pituitary and striatal tachykinins in response to testosterone: influence of prenatal melatonin.

Substance P (SP) and neurokinin A (NKA), members of the family of mammalian tachykinins, are involved in the regulation of many physiological functions and are widely distributed in mammalian tissues. In this report, the effects of prenatal melatonin on the postnatal developmental pattern of NKA, and SP, and on testosterone secretion were investigated. Also, tachykinin response to the administration of testosterone propionate (TP) was studied. The brain areas studied were medio-basal-hypothalamus, pituitary gland and striatum. Male rat offspring of control or melatonin treated mother rats were studied at different ages of the sexual development: infantile, juvenile or prepubertal periods, and pubertal period. Both groups received exogenous TP (control-offspring+TP and MEL-offspring+TP), or the vehicle (control-offspring+placebo and MEL-offspring+placebo). Hypothalamic concentrations of all peptides studied in control-offspring+placebo remained at low levels until the juvenile period, days 30-31 of age. After this age, increasing concentrations of these peptides were found, with peak values at puberty, 40-41 days of age, then declining until adulthood. In the MEL-offspring+placebo a different pattern of development was observed; hypothalamic concentrations of NKA and SP from the infantile period until the end of juvenile period were significantly higher than in control-offspring+placebo. TP administration exerted a more marked influence on MEL-offspring than on control-offspring and prevented the elevation in tachykinin concentrations associated with prenatal melatonin treatment. TP administration to control-offspring resulted in significantly reduced (P < 0.05) tachykinin concentration only at 40-41 days of age, and increased (P < 0.01) during infantile period as compared to control-offspring+placebo. Pituitary NKA concentrations were lower than in the hypothalamus. In control-offspring+placebo pituitary NKA levels did not show significant changes throughout sexual development. A different developmental pattern was observed in MEL-offspring+placebo, with significantly increased (P < 0.05) pituitary NKA concentrations at 35-36 days of age than in control-offspring+placebo. TP administration to control-offspring influenced pituitary NKA levels at the end of the infantile and pubertal periods, showing at both stages significantly higher (P < 0.05) NKA levels as compared to control-offspring+placebo. NKA levels in MEL-offspring+TP were only affected at 21-22 days of age, showing significantly increased (P < 0.01) values as compared to MEL-offspring+placebo. Striatal tachykinin concentrations in control-offspring did not undergo important modifications throughout sexual development, but during the prepubertal period they started to increase. Maternal melatonin and TP injections produced short-lived alterations during the infantile period. The results showed that prenatal melatonin delayed the postnatal testosterone secretion pattern until the end of the pubertal period and postnatal peptide secretion in brain structures. Consequently, all functions depending of the affected areas will in turn, be affected.

Animals↗